Chemical methods of synthesizing indoles, indolines, oxindoles, quinolines, isoquinolines, and isoquinolones are known. However, all such reactions generally operate only under heroic conditios and as well provide the desired heterocyclic product in low yields.
These above-referred-to compounds are extremely important compounds for a variety of reasons. For example, because of the very potent and diverse biological activity exhibited by indole and its various derivatives, this heterocyclic system has been the target of considerable attention in chemistry, biology and medicine. Indole derivatives are essential to both plants and animals. Skatole [3-methylindole], which can be isolated from various sources, is reported to have antidiuretic and tuberculostatic activity. Tryptophan, a naturally occurring amino acid is known to inhibit the growth of tuberculosis. Indole acetic acid is a major plant growth horomone and indomethacin has been reported to have antiinflammatory, antipyretic and analgesic activity.
Quinolines, too, are important. A number of quinoline alkaloids have been isolated from rutaceous plants. Among them as edulitine, folimine and folifidene. These alkaloids and many others bearing the quinoline ring systems possess important biological properties and have been the target of synthesis for many years. Though many synthetic approaches have been described, none are satisfactory for high yield, economic production.
Much interest in the isoquinoline alkaloids has also developed over the years and several new naturally occurring compounds have been found. Plants belonding to the fmaily Cactaceae are known to contain simple tetrahydroisoquinolines. Naturally occurring doryanine and doryfomine were isolated from sassafras tree. A number of isoquinoline alkaloids possessing important biological properties exist in nature and many of them have been synthesized in the laboratory.
In short, it can be seen that there is a real and continuing need for a convenient synthesis for the classes of compounds referred to herein. Many are useful as being derived from natural products, others are synthetically derived, but all are known to have physiological properties and exhibit a wide variety of pharmacological activity.
It is a primary objective of the present invention to prepare nitrogen heterocycles by palladium catalyzed intramolecular cyclization of haloaryl alkenes to provide in high yield compounds such as indoles, indolines, oxindoles, quinolines, isoquinolines, and isoquinolones.